Alzheimer's disease (AD) and Huntington's disease (HD) are both incurable degenerative brain diseases.
More specifically, AD is the most common form of dementia and HD, on the other hand, causes uncontrolled movements of the arms, legs, head, face, and upper body. HD also causes a decline in thinking and reasoning skills, including memory, concentration, judgement, and ability to plan and organize.
Both AD and HD are caused by aberrant aggregation of proteins or peptide. Indeed, AD is triggered by a malfunction of aggregated mutant β-amyloid peptide (Aβ) and HD arises from a toxic function of aggregated mutant huntingtin protein (HTT).
Human glutaminyl cyclase (QC) catalyzes cyclization of N-terminal residues of glutamine or glutamate to form pyroglutamate (pGlu) on Aβ and HTT. The pGlu-modified Aβ and pGlu-modified HTT thus formed are aggregative, neurotoxic, and resistant to proteolysis. They can initiate pathological cascades, resulting in development of AD or HD.
Inhibition of human QC has been found to diminish aggregation of both Aβ and HTT in cultured macrophage cells and in Drosophila and mouse models. See J. Pharmacol. Exp. Ther. 2017, 362, 119-130; J. Med. Chem. 2017, 60, 2573-2590; Nat. Med. 2008, 14(10), 1106-1111; and Nat. Chem. Bio. 2015, 11, 347-354.
As such, human QC is an emerging drug target for the treatment of AD or HD.
Currently, only a few drug candidates that inhibit QC are in clinical trials for treating AD or HD. There is a need to develop new QC inhibitors.
Earlier studies have shown that QC is a zinc-dependent enzyme. As such, compounds capable of chelating zinc at active sites of QC, e.g., benzimidazole compounds, are potential QC inhibitors.